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Structure Based Design of a Grp94-Selective Inhibitor: Exploiting a Key Residue in Grp94 To Optimize Paralog-Selective Binding

Journal Article · · Journal of Medicinal Chemistry
 [1];  [2];  [2];  [2];  [3];  [3];  [4]
  1. Hauptman-Woodward Medical Research Inst., Buffalo, NY (United States)
  2. Univ. of Kansas, Lawrence, KS (United States)
  3. Univ. of Notre Dame, IN (United States)
  4. Hauptman-Woodward Medical Research Inst., Buffalo, NY (United States); Univ. at Buffalo, NY (United States)
+ Show Author Affiliations
Grp94 and Hsp90, the ER and cytoplasmic hsp90 paralogs, share a conserved ATP-binding pocket that has been targeted for therapeutics. Paralog-selective inhibitors may lead to drugs with fewer side effects. In this work, we analyzed 1 (BnIm), a benzyl imidazole resorcinylic inhibitor, for its mode of binding. The structures of 1 bound to Hsp90 and Grp94 reveal large conformational changes in Grp94 but not Hsp90 that expose site 2, a binding pocket adjacent to the central ATP cavity that is ordinarily blocked. The Grp94:1 structure reveals a flipped pose of the resorcinylic scaffold that inserts into the exposed site 2. We exploited this flipped binding pose to develop a Grp94-selective derivative of 1. Our structural analysis shows that the ability of the ligand to insert its benzyl imidazole substituent into site 1, a different side pocket off the ATP binding cavity, is the key to exposing site 2 in Grp94.
Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Organization:
National Cancer Institute (NCI); National Institutes of Health (NIH); Richard and Mae Stone Goode Foundation of Buffalo
OSTI ID:
1502214
Journal Information:
Journal of Medicinal Chemistry, Journal Name: Journal of Medicinal Chemistry Journal Issue: 7 Vol. 61; ISSN 0022-2623
Publisher:
American Chemical Society (ACS)Copyright Statement
Country of Publication:
United States
Language:
ENGLISH

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Cited By (5)

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Structures of Hsp90α and Hsp90β bound to a purine‐scaffold inhibitor reveal an exploitable residue for drug selectivity journal June 2019
Inhibitors of the protein disulfide isomerase family for the treatment of multiple myeloma journal October 2018
Structural basis for species-selective targeting of Hsp90 in a pathogenic fungus journal January 2019
NECA derivatives exploit the paralog-specific properties of the site 3 side pocket of Grp94, the endoplasmic reticulum Hsp90 journal September 2019

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Related Subjects

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
Imidazoles
Ligands
Organic compounds
Pharmaceuticals
Substituents